Human Fanconi anemia monoubiquitination pathway promotes homologous DNA repair

Nakanishi, Koji; Yang, Yun‐Gui; Pierce, Andrew J.; Taniguchi, Toshiyasu; Digweed, Martin; D’Andrea, Alan D.; Wang, Zhaoqi; Jasin, Maria

doi:10.1073/pnas.0407796102

Cited by 357 publications

(365 citation statements)

References 41 publications

Supporting

Mentioning

339

Contrasting

Order By: Relevance

“…Although the purpose of FANCD2 monoubiquitination remains unknown, it seems likely that it has a role in HR as BRCA1, BRCA2, RAD51, and NBS1 have all been implicated in this process (Moynahan et al 1999;Tutt et al 2001;Kobayashi et al 2004). In support of this hypothesis, cell lines deficient in the FA pathway have been reported to have defective HR (Donahue et al 2003;Yamamoto et al 2003;Niedzwiedz et al 2004;Nakanishi et al 2005). In general, disruption of upstream FA proteins, such as FANCA and FANCG (Yamamoto et al 2003) result in milder HR defects than disruption of BRCA2/FANCD1 (Moynahan et al 2001b), suggesting that the FA chromatin-associated complex 2 is largely responsible for the DNA repair functions of the FA pathway.…”

Section: Recruitment Of Dna Repair Proteinssupporting

confidence: 58%

The Fanconi Anemia/BRCA pathway: new faces in the crowd

Kennedy¹,

D’Andrea²

2005

Genes Dev.

Self Cite

364

345

View full text Add to dashboard Cite

Over the past few years, study of the rare inherited chromosome instability disorder, Fanconi Anemia (FA), has uncovered a novel DNA damage response pathway. Through the cooperation of multiple proteins, this pathway regulates a complicated cellular response to DNA cross-linking agents and other genotoxic stresses. In this article we review recent data identifying new components of the FA pathway that implicate it in several aspects of the DNA damage response, including the direct processing of DNA, translesion synthesis, homologous recombination, and cell cycle regulation. We also discuss new findings that explain how the FA pathway is regulated through the processes of ubiquitination and deubiquitination. We then consider the clinical implications of our current understanding of the FA pathway, particularly in the development and treatment of malignancy in heterozygous carriers of FA mutations or in patients with sporadic cancers. We consider how recent studies of p53-mediated apoptosis and loss of p53 function in models of FA may help explain the clinical features of the disease and finally present a hypothesis to account for the specificity of the FA pathway in the response to DNA cross-links.

show abstract

Section: Recruitment Of Dna Repair Proteinssupporting

confidence: 58%

The Fanconi Anemia/BRCA pathway: new faces in the crowd

Kennedy¹,

D’Andrea²

2005

Genes Dev.

Self Cite

364

345

View full text Add to dashboard Cite

show abstract

“…First, FA-D1 patients are much more susceptible to cancer, including early onset leukemia and solid tumor, than other subtypes of FA (51,52). Second, a recent study provided evidence that HR defects in BRCA mutant human cells are much larger in size than in classical FA cells (fancc, fancg, and fancd2) (9). Furthermore, these FA genes, but not BRCA2, are necessary for one type of HR repair, i.e.…”

Section: Discussionmentioning

confidence: 99%

Functional Interplay between BRCA2/FancD1 and FancC in DNA Repair

Kitao

Yamamoto²,

Matsushita

et al. 2006

Journal of Biological Chemistry

View full text Add to dashboard Cite

A rare hereditary disorder, Fanconi anemia (FA), is caused by mutations in an array of genes, which interact in a common FA pathway/network. These genes encode components of the FA "core" complex, a key factor FancD2, the familial breast cancer suppressor BRCA2/FancD1, and Brip1/FancJ helicase. Although BRCA2 is known to play a pivotal role in homologous recombination repair by regulating Rad51 recombinase, the precise functional relationship between BRCA2 and the other FA genes is unclear. Here we show that BRCA2-dependent chromatin loading of Rad51 after mitomycin C treatment was not compromised by disruption of FANCC or FANCD2. Rad51 and FancD2 form colocalizing subnuclear foci independently of each other. Furthermore, we created a conditional BRCA2 truncating mutation lacking the C-terminal conserved domain (CTD) (brca2⌬CTD), and disrupted the FANCC gene in this background. The fancc/ brca2⌬CTD double mutant revealed an epistatic relationship between FANCC and BRCA2 CTD in terms of x-ray sensitivity. In contrast, levels of cisplatin sensitivity and mitomycin C-induced chromosomal aberrations were increased in fancc/brca2⌬CTD cells relative to either single mutant. Taken together, these results indicate that FA proteins work together with BRCA2/Rad51-mediated homologous recombination in double strand break repair, whereas the FA pathway plays a role that is independent of the CTD of BRCA2 in interstrand cross-link repair. These results provide insights into the functional interplay between the classical FA pathway and BRCA2.

show abstract

“…In contrast, in higher eukaryotes, UBC13 and MMS2 seem to function in HR in addition to their roles in PRR (23,24). To determine whether SHPRH and HLTF are involved in HR, we used a recombination reporter assay (DR-GFP reporter assay), which can measure the frequency of HR between tandem GFP repeats with inactivating mutations (25). Transient expression of the I-SceI endonuclease in these cells generates a single DSB that is repaired by HR to produce a functional GFP.…”

Section: Shprh and Hltf Are Not Directly Involved In Homologous Recommentioning

confidence: 99%

Polyubiquitination of proliferating cell nuclear antigen by HLTF and SHPRH prevents genomic instability from stalled replication forks

Motegi

Liaw

Lee

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

251

269

View full text Add to dashboard Cite

C hronic stalling of DNA replication forks by DNA damage such as UV irradiation, ionizing irradiation, chemicals, and reactive cellular metabolites impedes the progression of the cell cycle and eventually causes cell death. To circumvent such situations, cells have evolved the postreplication repair (PRR) pathway that bypasses DNA lesions to resolve stalled forks without removing the actual damage (1). In budding yeast Saccharomyces cerevisiae, PRR is carried out by 2 distinct pathways: translesion synthesis (TLS) and template switching (TS) (Fig. 1A). TLS uses multiple low-fidelity TLS polymerases to incorporate nucleotides across DNA lesions (2, 3). Switching from replicative polymerases ␦ or to TLS polymerases is promoted through the interaction between monoubiquitinated PCNA at lysine 164 (K164) and a ubiquitin-binding motif in TLS polymerases-a mechanism conserved from the budding yeast to human. The monoubiquitination of PCNA at K164 requires the RING-type ubiquitin ligase Rad18 (E3) and the ubiquitinconjugating enzyme Rad6 (E2).The TS pathway bypasses DNA damage by switching a stalled replicating end to the nascent daughter strand of the sister chromatid (1, 4). This pathway involves a lysine 63 (K63)-linked polyubiquitin chain that is further added onto the monoubiquitinated PCNA by Rad5 (E3) along with the Ubc13-Mms2 (E2 and E2 variant, respectively) heterodimer complex (Fig. 1 A). Distinct from the K48-linked polyubiquitination leading to protein degradation, the K63-linked polyubiquitination of PCNA is thought to promote TS in a proteasome-independent manner (5).The importance of the TLS pathway in the suppression of mammalian tumorigenesis emerged with the identification of a mutation in TLS polymerase in patients with the variant form of xeroderma pigmentosum and from studies with mouse models (6, 7). Despite the presence of UBC13 and MMS2 homologues in humans, the importance of the TS pathway is less clear in mammals because K63-linked polyubiquitination of PCNA, a hallmark event for the TS pathway, had not been observed until recently (8-10). We recently identified human SHPRH, which possesses SWI2/SNF2 and RING domains with similar architecture to the yeast Rad5 as a functional homologue of yeast Rad5 (9). Specifically, we demonstrated the in vivo activity of SHPRH in promoting a K63-linked polyubiquitination of PCNA as well as physical interactions of SHPRH with PCNA, RAD18, and UBC13. Depletion of SHPRH increases genomic instability after genotoxic stress. Consistent with our work, another study also demonstrated that SHPRH could polyubiquitinate PCNA in vitro (11).In the present study, we demonstrated that ectopic expression of HLTF/SMARCA3/RUSH/HIP116/Zbu1 (hereafter, HLTF) enhanced PCNA polyubiquitination in vivo. Depletion of SHPRH or HLTF significantly reduced polyubiquitination of chromatin-bound PCNA upon treatment of cells with DNA-damaging agents that cause stalled DNA replication forks. Furthermore, Hltf-deficient mouse embryonic fibroblasts (MEFs) showed elevated chromosome breaks an...

show abstract

Human Fanconi anemia monoubiquitination pathway promotes homologous DNA repair

Cited by 357 publications

References 41 publications

The Fanconi Anemia/BRCA pathway: new faces in the crowd

The Fanconi Anemia/BRCA pathway: new faces in the crowd

Functional Interplay between BRCA2/FancD1 and FancC in DNA Repair

Polyubiquitination of proliferating cell nuclear antigen by HLTF and SHPRH prevents genomic instability from stalled replication forks

Contact Info

Product

Resources

About